Amino Acid Compositions

ABSTRACT

Methods for increasing athletic performance, distribution of various Amino Acids to muscles, and solubility of various Amino Acids in a human or animal by administering an amino acid composition that includes: at least one constituent selected from the group consisting of a nitrate, a nitrite, and both; and at least one constituent amino acid selected from the group consisting of Arginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, Proline, Tyrosine, and Phenylalanine

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of the earlierU.S. Utility patent application to Ronald Kramer, et. al. entitled“Amino Acid Compounds,” application Ser. No. 12/336,938, filed Dec. 17,2008, now pending, which is a continuation application of the earlierU.S. Utility patent application to Ronald Kramer, et. al. entitled“Amino Acid Compounds,” application Ser. No. 11/950,273, filed Dec. 4,2007, now U.S. Pat. No. 7,777,074, which application claims the benefitof the filing date of U.S. Provisional Patent Application 60/973,229entitled “Amino Acid Compounds” to Ronald Kramer, et. al., filed on Sep.18, 2007, the disclosures of all of which being hereby incorporatedentirely herein by reference.

BACKGROUND

1. Technical Field

Aspects of this document relate generally to amino acid compositions.

2. Background

It is desirable to design new amino acid compositions that haveproperties lacking in conventional amino acids, conventional nitrates,and conventional nitrites alone.

In one aspect, an amino acid composition is disclosed including anitrate or nitrite or both mixed with at least one amino acid selectedfrom the group consisting of Arginine, Agmatine, Beta Alanine,Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine,Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine, Lysine,Methionine, Proline, Tyrosine, and Phenylalanine.

The Amino Acid Composition may further include a pharmaceuticallyacceptable additive. The additive may be a carrier, an excipient, abinder, a colorant, a flavoring agent, a preservative, a buffer, adilutant, and/or combinations thereof. The Amino Acid Composition may bein the form of a capsule, tablet, pill, liquid, liquid suspension,vapor, gas, powder, granulate or pulverulence.

In another aspect, a method is disclosed for enhancing athleticperformance. The method includes administering a pharmaceuticallyeffective amount to a human or animal of an amino acid compositionincluding a nitrate or nitrite or both mixed with at least one aminoacid selected from the group consisting of Arginine, Agmatine, BetaAlanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine,Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine,Lysine, Methionine, Proline, Tyrosine, and Phenylalanine.

In still another aspect, a method is disclosed for increasingdistribution of Amino Acids to muscles. The method includesadministering a pharmaceutically effective amount to a human or animalof an amino acid composition including a nitrate or nitrite or bothmixed with at least one amino acid selected from the group consisting ofArginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine,L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, Valine, AsparticAcid, Cysteine, Glycine, Lysine, Methionine, Proline, Tyrosine, andPhenylalanine.

In even another aspect, a method is disclosed for increasing solubilityof Amino Acids. The method includes administering a pharmaceuticallyeffective amount to a human or animal of an amino acid compositionincluding a nitrate or nitrite or both mixed with at least one aminoacid selected from the group consisting of Arginine, Agmatine, BetaAlanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine,Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine,Lysine, Methionine, Proline, Tyrosine, and Phenylalanine.

The foregoing and other aspects, features, and advantages will beapparent to those artisans of ordinary skill in the art from theDESCRIPTION and DRAWINGS, and from the CLAIMS.

DESCRIPTION Overview, Terminology and Definitions:

In describing implementations of an Amino Acid Compound and Composition,the following terminology will be used in accordance with thedefinitions and explanations set out below. Notwithstanding, otherterminology, definitions, and explanations may be found throughout thisdocument, as well.

As used herein, “Amino Acid” is a term used in its broadest sense andmay refer to an Amino Acid in its many different chemical formsincluding a single administration Amino Acid, its physiologically activesalts or esters, its combinations with its various salts, itstautomeric, polymeric and/or isomeric forms, its analog forms, itsderivative forms, its products of biosynthesis, and/or itsdecarboxylation products. Amino Acids comprise, by way of non-limitingexample: Agmatine, Beta Alanine, Arginine, Asparagine, Aspartic Acid,Cysteine, Glutamine, Glutamic Acid, Glycine, Histidine, L-Histidine,Leucine, Isoleucine, Lysine, Methionine, PhenylBeta Alanine, Proline,Serine, Threonine, Tryptophan, Tyrosine, Valine, Citrulline, Creatine,Glutamine, Norvaline, Ornithine, and Phenylalanine.

Compounds containing both a carboxyl group and an amino group aretypically known as Amino Acids. Amino Acids typically have the basicformula X—R, wherein X is:

Amino Acids typically differ from one another with respect to thestructure of the R group. It is the structure of the R group thattypically determines the individuality and character of each Amino Acid.

For example, the R group for the Amino Acid Arginine is:

Arginine is characterized as a nonessential Amino Acid. Specifically,Arginine can be independently manufactured by the human body, and doesnot need to be obtained directly through dietary intake. Arginine playsa significant role in healing, cell division, immune function, theelimination of ammonia from the body and the release of hormones.Arginine is presently used in the dietary supplement industry tosupplement Arginine production in the body. Arginine is also presentlyused in the dietary supplement industry to boost Human Growth Hormone(HGH) production, increase vasodilation, enhance blood circulation,increase oxygen flow to the muscles, and boost Nitric Oxide (NO)production. Various supplemental Arginine forms are available in theconsumer marketplace.

The vasodilating effect of ingested Arginine takes considerable time tomanifest since Arginine requires extensive metabolism to yield NitricOxide (NO). Additionally, considerable amounts of Arginine are requiredto produce a significant vasodilating effect, with common doses rangingfrom eight to twenty-four grams per day.

The R group for the Amino Acid Citrulline is:

Citrulline is an alpha-Amino Acid naturally occurring in the human body,and does not need to be obtained directly through dietary intake. Invivo, Citrulline is made from the Amino Acid Ornithine, along withcarbamoyl phosphate in one of the central reactions in the Urea Cycle.Citrulline is also produced during the metabolism of Arginine in thebody. Citrulline is presently used in the dietary supplement industry tosupplement Citrulline production in the body. By itself, Citrulline hasno vasodilating properties. Citrulline is also water insoluble, whichreduces its bioavailability and limits the forms in which Citrulline maybe effectively used.

The R group for the Amino Acid Creatine is:

Creatine is a nonessential Amino Acid and is also a nitrogenous organicacid. Creatine is independently manufactured by the human body, and doesnot need to be obtained directly through dietary intake. Creatine playsa significant role in providing muscles with energy. Creatine ispresently used in the dietary supplement industry to supplement Creatineproduction in the body. Creatine is also presently used in the dietarysupplement industry to increase muscle-mass gains, improve athleticperformance and strength. Creatine, by itself, has no vasodilatingproperties. Creatine is also water insoluble, which reduces itsbioavailability and limits the forms in which Creatine may beeffectively used.

The R group for the Amino Acid Glutamine is:

Glutamine is a nonessential Amino Acid. Glutamine is the most abundantnaturally occurring, non-essential amino acid in the human body and isfound circulating in the blood, as well as stored in the skeletalmuscles. Glutamine plays a significant role in protein synthesis, musclegrowth, and wound healing. Glutamine is presently used in the dietarysupplement industry to supplement Glutamine production in the body.Glutamine is also presently used in the dietary supplement industry tomaintain the body's Glutamine pool. Glutamine, by itself, has novasodilating properties. Glutamine is also water insoluble, whichreduces its bioavailability and limits the forms in which Glutamine maybe effectively used. Additionally, Glutamine inhibits Nitric Acid (NO)production through downregulation of eNOS synthase.

The R group for the Amino Acid Leucine is:

Leucine is an essential Amino Acid, meaning that Leucine is notsynthesized in vivo in animals. Accordingly, Leucine must be ingested,usually as a component of proteins consumed directly through dietaryintake. Leucine plays a significant role in muscle protein synthesis.Leucine can also inhibit protein degradation in skeletal muscle, as wellas in the liver. Leucine is presently used in the dietary supplementindustry to supplement dietary Leucine sources. Leucine is alsopresently used in the dietary supplement industry to promote anabolismand stimulate muscle protein synthesis. Leucine, by itself, has novasodilating properties. Leucine is also water insoluble, which reducesits bioavailability and limits the forms in which Leucine may beeffectively used.

The R group for the Amino Acid Norvaline is:

Norvaline is a nonessential Amino Acid. Specifically, Norvaline can beindependently manufactured by the human body, and does not need to beobtained directly through dietary intake. Norvaline is presently used inthe dietary supplement industry to supplement Norvaline production inthe body. Norvaline is also presently used in the dietary supplementindustry to inhibit the enzyme arginase and thus reduce the conversionof Arginine to urea. Norvaline, by itself, has no vasodilatingproperties, although it enhances the vasodilating properties ofArginine. Norvaline is also water insoluble, which reduces itsbioavailability and limits the forms in which Leucine may be effectivelyused.

The R group for the Amino Acid Ornithine is:

Ornithine is a non-essential Amino Acid. That is, Ornithine isindependently manufactured by the human body, and does not need to beobtained directly through dietary intake. Ornithine plays a significantrole in the synthesis of polyamines, specifically via the action ofOrnithine decarboxylase. Ornithine is presently used in the dietarysupplement industry to supplement dietary Ornithine sources. Ornithineis also presently used in the dietary supplement industry to enhance thevasodilating properties in a series of products commonly known as “NOBoosters.” Ornithine exerts its vasodilating effect only by in vivoconversion to Arginine and then by following the pathway that convertsArginine to Nitric Acid (NO). Many grams of Ornithine, and aconsiderable amount of time, are required in order to assert itsvasodilating effect.

The R group for the Amino Acid Histidine is:

Histidine is a naturally-occurring Amino Acid and is coded for in DNA.Relatively small shifts in cellular pH will change the electrical chargeof Histidine. For this reason, Histidine finds its way into considerableuse as a coordinating ligand in metalloproteins, and also as a catalyticsite in certain enzymes. Histidine is currently used in the dietarysupplement industry to support carnosine production. Histidine, byitself, has no vasodilating properties. Additionally, Histidine is verypoorly water soluble, a fact that limits its bioavailability andutility. Histidine is presently used in the dietary supplement industryin the forms of single administration Histidine and Histidine HCl.

The R group for the Amino Acid Beta Alanine is:

Beta Alanine is the only naturally-occurring Beta Amino Acid. A BetaAmino Acid is one in which the Amino group is located at the betaposition (i.e. two atoms away) from the Carboxyl group. Beta Alanine isformed in vivo through the degradation of dihydrouracil and carnosine.Beta Alanine is the rate-limiting precursor of carnosine. Therefore,carnosine levels are limited by the amount of available Beta Alanine.Beta Alanine, by itself, has no vasodilating properties. Additionally,Beat Alanine is somewhat water soluble, which limits its bioavailabilityand utility. Beta Alanine is presently used in the dietary supplementindustry to support carnosine production.

The chemical structure of Agmatine is:

Agmatine is the decarboxylation product of the Amino Acid Arginine andis an intermediate in polyamine biosynthesis. Agmatine is synthesized inthe brain and stored in synaptic vesicles in regionally selectiveneurons. Agmatine is released by depolarization and is inactivated byagmatinase. Agmatine binds to alpha2-adrenoceptors and imidazolinebinding sites. Agmatine likewise blocks N-methyl-D-aspartic acid (NMDA)receptor channels and other ligand-gated cationic channels.Additionally, agmatine inhibits nitric oxide synthase, and induces therelease of some peptide hormones. Agmatine modulates nitric oxidethrough various mechanisms. Agmatine stimulates some types of nitricoxide synthase (NOS) while inhibiting others. Agmatine inhibits NitricOxide production by inhibiting NOS. Agmatine is presently used in thedietary supplement industry in the forms of single administrationAgmatine and Agmatine Sulfate.

As used herein, “Composition” is a term used in its broadest sense andmay refer to a mixture of constituent substances or ingredients.“Mixture” is a term used in its broadest sense and may refer to two ormore constituent substances or ingredients (chemical species present ina system) which have been combined (not necessarily in fixed proportionsand not necessarily with chemical bonding and not necessarily so thateach substance retains its own chemical identity). Mixtures can be theproduct of a blending or mixing of chemical substances like elements andcompounds, without chemical bonding or other chemical change, so thateach ingredient substance retains its own chemical properties andmakeup. Mixtures can be either homogeneous or heterogeneous. Ahomogeneous mixture is a type of mixture in which the composition isuniform. A heterogeneous mixture is a type of mixture in which thecomposition can easily be identified, as there are two or more phasespresent. A homogeneous mixture in which there is both a solute andsolvent present is also a solution.

A “Compound” is a term used in its broadest sense and may refer to achemical substance comprising two or more different chemically bondedchemical constituent elements or ingredients, with a fixed ratio orproportion by weight. The atoms within a compound can be held togetherby a variety of interactions, ranging from covalent bonds toelectrostatic forces in ionic bonds. The physical and chemicalproperties of compounds are different from those of their constituentelements. This is one of the main criteria for distinguishing a compoundfrom a mixture of elements or other substances because a mixture'sproperties are generally closely related to and dependent on theproperties of its constituents. However, some mixtures are so intimatelycombined that they have some properties similar to compounds. Anothercriterion for distinguishing a compound from a mixture is that theconstituents of a mixture can usually be separated by simple, mechanicalmeans such as filtering, evaporation, or use of a magnetic force, butthe components of a compound can only be separated by a chemicalreaction. Conversely, mixtures can be created by mechanical means alone,but a compound can only be created (either from elements or from othercompounds, or a combination of the two) by a chemical reaction.

Thus, for purposes of this disclosure, “Composition” may refer to amixture of at least one Amino Acid in combination with at least aNitrate, a Nitrite, or both from any source.

As used herein, “Nitrate” is a term used in its broadest sense and mayrefer to an Nitrate in its many different chemical forms including asalt of Nitric Acid, a single administration Nitrate, itsphysiologically active salts or esters, its combinations with itsvarious salts, its tautomeric, polymeric and/or isomeric forms, itsanalog forms, and/or its derivative forms. Nitrate comprises, by way ofnon-limiting example, many different chemical forms including dinitrateand trinitrate. Nitrates may be salts, or mixed salts, of Nitric Acid(HNO₃) and comprise one Nitrogen atom and three Oxygen atoms (NO₃). Forthe exemplary purposes of this disclosure, Nitrate may comprise salts ofNitrate such as sodium nitrate, potassium nitrate, barium nitrate,calcium nitrate, and the like. For the exemplary purposes of thisdisclosure, Nitrate may include mixed salts of Nitrate such as nitrateorotate, and the like. Additionally, for the exemplary purposes of thisdisclosure, Nitrate may comprise nitrate esters such as nitroglycerine,and the like. Furthermore, for the exemplary purposes of thisdisclosure, nitrates that are commonly used in supplement industry areappropriate sources of nitrates, such as juice, extract, powder and thelike of Cabbage, Spinach, Beetroot, Artichoke, Asparagus, Broad Bean,Eggplant, Garlic, Onion, Green Bean, Mushroom, Pea, Pepper, Potato,Summer Squash, Sweet Potato, Tomato, Watermelon, Broccoli, Carrot,Cauliflower, Cucumber, Pumpkin, Chicory, Dill, Turnip, Savoy Cabbage,Celeriac, Chinese Cabbage, Endive, Fennel, Kohlrabi, Leek, Parsley,Celery, Cress, Chervil, Lettuce, Rocket (Rucola), and the like.

As used herein, “Nitrite” is a term used in its broadest sense and mayrefer to an Nitrite in its many different chemical forms including asalt of Nitrous Acid, a single administration Nitrite, itsphysiologically active salts or esters, its combinations with itsvarious salts, its tautomeric, polymeric and/or isomeric forms, itsanalog forms, and its derivative forms. Nitrite comprises, by way ofnon-limiting example, many different chemical forms including dinitriteand trinitrite. Nitrites may be salts, or mixed salts, of Nitrous Acid(HNO₂) and comprise one Nitrogen atom and two Oxygen atoms (NO₂). Forthe exemplary purposes of this disclosure, Nitrite may comprise salts ofNitrite such as sodium nitrite, potassium nitrite, barium nitrite,calcium nitrite, and the like. For the exemplary purposes of thisdisclosure, Nitrite may comprise mixed salts of Nitrite such as nitriteorotate, and the like. Additionally, for the exemplary purposes of thisdisclosure, Nitrite may comprise nitrite esters such as amyl nitrite,and the like. Furthermore, for the exemplary purposes of thisdisclosure, natural sources of Nitrites that are commonly used insupplement industry are appropriate sources of Nitrites, such as juice,extract, powder and the like of Cabbage, Spinach, Beetroot, Artichoke,Asparagus, Broad Bean, Eggplant, Garlic, Onion, Green Bean, Mushroom,Pea, Pepper, Potato, Summer Squash, Sweet Potato, Tomato; Watermelon,Broccoli, Carrot, Cauliflower, Cucumber, Pumpkin, Chicory, Dill, Turnip,Savoy Cabbage, Celeriac, Chinese Cabbage, Endive, Fennel, Kohlrabi,Leek, Parsley, Celery, Cress, Chervil, Lettuce, Rocket (Rucola), and thelike.

Nitrates and Nitrites are commercially available in variouspreparations, including natural preparations, and are used in variousapplications. In the case of ingestion by humans, Nitrate (NO₃) istypically reduced to Nitrite (NO₂) in the epithelial cells of bloodvessels. In vivo, Nitrite (NO₂) reacts with a thiol donor, principallyglutathione, to yield Nitric Oxide (NO).

As used herein, “pharmaceutically acceptable additive” or “additive” areterms used in their broadest sense. Particular implementations of thecompositions described in this document may also comprise an additive(e.g. one of a solubilizer, an enzyme inhibiting agent, ananticoagulant, an antifoaming agent, an antioxidant, a coloring agent, acoolant, a cryoprotectant, a hydrogen bonding agent, a flavoring agent,a plasticizer, a preservative, a sweetener, a thickener, andcombinations thereof) and/or a carrier (e.g. one of an excipient, alubricant, a binder, a disintegrator, a diluent, an extender, a solvent,a suspending agent, a dissolution aid, an isotonization agent, abuffering agent, a soothing agent, an amphipathic lipid delivery system,and combinations thereof). These additives may be solids or liquids, andthe type of additive may be generally chosen based on the type ofadministration being used. Those of ordinary skill in the art will beable to readily select suitable pharmaceutically effective additivesfrom the disclosure in this document. In particular implementations,pharmaceutically acceptable additives may include, by non-limitingexample, calcium phosphate, cellulose, stearic acid, croscarmelosecellulose, magnesium stearate, and silicon dioxide.

As used in this document, “pharmaceutically effective” is a phrase usedin its broadest sense, including, by non-limiting example, effective ina clinical trial, for a specific patient, or only placebo-effective.

As used in this document, “Pharmaceutically acceptable” is a phrase usedin its broadest sense and may describe ingredients of a pharmaceuticalcomposition that meet Food and Drug Administration (FDA) standards,United States Pharmacopeial Standards (USP), US Department ofAgriculture (USDA) standards for food-grade materials, commonly acceptedstandards of the nutritional supplement industry, industry standards,botanical standards, or standards established by any individual. Thesestandards may delineate acceptable ranges of aspects of ingredients of apharmaceutical composition such as edibility, toxicity, pharmacologicaleffect, or any other aspect of a chemical, composition, or preparationused in implementations of a pharmaceutical composition.

Components/Compounds/Compositions

A first implementation is an Arginine compound of the formula:

wherein;

-   R is the Arginine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Arginine Nitrate bycombining nitric acid and Arginine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Arginine Dinitrate or Arginine Trinitrate. An alternativeimplementation may comprise using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Arginine Nitrite. Arginine Nitrite has thesame effects as Arginine Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of ArginineNitrate-Orotate.

A second implementation is a Citrulline compound of the formula:

wherein;

-   R is the Citrulline group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Citrulline Nitrate bycombining nitric acid and Citrulline, mixing with water or anotherpolar, easily evaporated solvent like methanol, alcohol, pyridine, andthe like, and leaving to crystallize. Further nitratization can takeplace, yielding Citrulline Dinitrate or Citrulline Trinitrate. Analternative implementation may comprise using Nitrous Acid (HNO₂)instead of Nitric Acid (HNO₃), thus yielding Citrulline Nitrite.Citrulline Nitrite has the same effects as Citrulline Nitrate, the onlydifference being that it requires one less step to yield Nitric Oxide(NO—). Mixed salts may also be used, such as in the non-limiting exampleof Citrulline Nitrate-Orotate.

A third implementation is a Creatine compound of the formula:

wherein;

-   R is the Creatine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Creatine Nitrate bycombining nitric acid and Creatine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Creatine Dinitrate or Creatine Trinitrate. An alternativeimplementation may comprise using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Creatine Nitrite. Creatine Nitrite has thesame effects as Creatine Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of CreatineNitrate-Orotate.

A fourth implementation is a Glutamine compound of the formula:

wherein;

-   R is the Glutamine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Glutamine Nitrate bycombining nitric acid and Glutamine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Glutamine Dinitrate or Glutamine Trinitrate. An alternativeimplementation comprises using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Glutamine Nitrite. Glutamine Nitrite has thesame effects as Glutamine Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of GlutamineNitrate-Orotate.

A fifth implementation is a Leucine compound of the formula:

wherein;

-   R is the Leucine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Leucine Nitrate bycombining nitric acid and Leucine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Leucine Dinitrate or Leucine Trinitrate. An alternativeimplementation comprises substituting the Amino Acids Valine orIsoleucine for Leucine. Another alternative implementation comprisessubstituting Nitrous Acid (HNO₂) for Nitric Acid (HNO₃), thus yieldingLeucine Nitrite. Leucine Nitrite has the same effects as LeucineNitrate, the only difference being that it requires one less step toyield Nitric Oxide (NO—). Mixed salts may also be used, such as in thenon-limiting example of Leucine Nitrate-Orotate.

A sixth implementation is a Norvaline compound of the formula:

wherein;

-   R is the Norvaline group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Norvaline Nitrate bycombining nitric acid and Norvaline, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Norvaline Dinitrate or Norvaline Trinitrate. An alternativeimplementation comprises substituting Nitrous Acid (HNO₂) for NitricAcid (HNO₃), thus yielding Norvaline Nitrite. Norvaline Nitrite has thesame effects as Norvaline Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of NorvalineNitrate-Orotate.

A seventh implementation is an Ornithine compound of the formula:

wherein;

-   R is the Ornithine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Ornithine Nitrate bycombining nitric acid and Ornithine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Ornithine Dinitrate or Ornithine Trinitrate. An alternativeimplementation comprises using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Ornithine Nitrite. Ornithine Nitrite has thesame effects as Ornithine Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of OrnithineNitrate-Orotate.

An eighth implementation is a Histidine compound of the formula:

wherein;

-   R is the Histidine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Histidine Nitrate bycombining nitric acid and Histidine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Histidine Dinitrate or Histidine Trinitrate. An alternativeimplementation comprises using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Histidine Nitrite. Histidine Nitrite has thesame effects as Histidine Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of HistidineNitrate-Orotate.

A ninth implementation is a Beta Alanine compound of the formula:

wherein;

-   R is the Beta Alanine group identified and defined above;-   X is the Amino Acid base identified and defined above; and-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Beta Alanine Nitrate bycombining nitric acid and Beta Alanine, mixing with water or anotherpolar, easily evaporated solvent like methanol, alcohol, pyridine, andthe like, and leaving to crystallize. Further nitratization can takeplace, yielding Beta Alanine Dinitrate or Beta Alanine Trinitrate. Analternative implementation comprises using Nitrous Acid (HNO₂) insteadof Nitric Acid (HNO₃), thus yielding Beta Alanine Nitrite. Beta AlanineNitrite has the same effects as Beta Alanine Nitrate, the onlydifference being that it requires one less step to yield Nitric Oxide(NO—). Mixed salts may also be used, such as in the non-limiting exampleof Beta Alanine Nitrate-Orotate.

A tenth implementation is an Agmatine compound of the formula:

wherein;

-   Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Agmatine Nitrate bycombining nitric acid and Agmatine, mixing with water or another polar,easily evaporated solvent like methanol, alcohol, pyridine, and thelike, and leaving to crystallize. Further nitratization can take place,yielding Agmatine Dinitrate or Agmatine Trinitrate. An alternativeimplementation comprises using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Agmatine Nitrite. Agmatine Nitrite has thesame effects as Agmatine Nitrate, the only difference being that itrequires one less step to yield Nitric Oxide (NO—). Mixed salts may alsobe used, such as in the non-limiting example of AgmatineNitrate-Orotate.

Other implementations involve compositions instead of compounds. Usingan independent source of nitrates and/or nitrites that is mixed with anyof the amino acids disclosed in this document to form a composition canobtain substantially the same effects as the amino acid nitrate ornitrite compounds discussed in this document.

Such an amino acid composition might be depicted by the formula X−R+Y.“X−R” represents an amino acid as discussed previously and “Y”represents a Nitrate and/or Nitrite. But instead of forming a compound,they are mixed together (represented by the “+”) to form a composition.

For the exemplary purposes of this disclosure, following is a variety ofspecific examples of amino acid compositions.

Composition 1: Creatine Nitrate 100-1000 mg in capsules. Dosage is 3capsules twice daily.

Composition 2 (Powder Form): Serving Size: 4 grams. Creatine Nitrate3-3.5 grams. Vitamin C 500-1000 mg.

Composition 3 (Sports Drink): 0.5-3 Grams Arginine Nitrate. 0.5-2 GramsTaurine. 1-3 grams Sugar or appropriate Sweetener. Artificial Coloring.Purified Water till 500 ml of total Volume.

Composition 4 (sublingual tablets; amounts are per tablet): AgmatineNitrate 10-100 mg. Maltulose 200 mg. Artificial Cherry Flavor. MeltMaltulose, add in slowly the Agmatine Nitrate and the flavor, and pourin the tablet machine.

Composition 5 (Tablets Containing Arginine and Potassium Nitrate forBlood Pressure support). Per tablet: Arginine 250-700 mg. PotassiumNitrate 50-500 mg. Corn Starch till the desired volume for the tabletmachine is obtained.

Composition 6 (for healthy blood pressure support): 500-1000 mg Arginine(As arginine nitrate)+250-500 mg Celery Seed Extract+100-300 mg DriedGarlic Powder in airseal Capsules.

Composition 7 (For improved Sexual Performance): 500-1000 mg gramsAgmatine+1-2 grams D-aspartic Acid (as D-Aspartic Acid Nitrate)+1-2grams dried onion powder (onion also increases testosterone) incapsules.

Composition 8 (Improved Strength): Creatine(As Creatine Malate) 2-3grams and Calcium Nitrate 500 mg.

Composition 9 (Improved Muscle Endurance Sports Drink): Beta Alanine 1-2grams+Citrulline (As Citrulline Nitrate) 250-500 mg+Potassium Nitrate100-200 mg+Sodium Nitrate 50-100 mg+Magnesium Nitrate 200 mg ArtificialCOlouring Sweetener and flavour Purified Water till 500 ml.

Composition 10 (Improved Muscle anabolism and recovery): Leucine 1-5grams Isoleucine 1-2 grams Valine 1-2 grams Spinach Extract (Standarizedfor nitrate content and ecdysterone content minimum 1% and 10%respectively) 5 grams.

Composition 11 (Improved Mental Performance): 500-1000 mgTyrosine+250-500 mg Phenylalanine (as Phenylalanine Nitrate)+1000-2000mg Glycine+200-300 mg Lithium Nitrate+300-600 mg Hystidine In TimeRelease Tablets.

Composition 12 (Growth Hormone Support): Arginine 2-4 grams+Ornithine1-2 grams+Magnesium Nitrate 500 mg.

Composition 13 (Hair Growth Support As External Use Cream): LysineNitrite 1 gram Hydroxyproline Nitrate 5 grams Methionine nitrate 5 gramsEuserine Cream Base 100 grams.

Composition 14 (Immune Support effervescent tabs): Glutamine 400-800 mgHystidine (As histidine nitrate) 250-500 mg Cysteine (As N-AcetylCysteine) 200-300 mg PArsley Powder (Standarized for Vitamin C andnitrate) 125-250 mg.

Administration and Dosage Forms

Compounds, Compositions and/or formulations may be administered in anyform, including one of a capsule, a cachet, a pill, a tablet, a powder,a granule, a pellet, a bead, a particle, a troche, a lozenge, apastille, a solution, an elixir, a syrup, a tincture, a suspension, anemulsion, a mouthwash, a spray, a drop, an ointment, a cream, a gel, apaste, a transdermal patch, a suppository, a pessary, cream, a gel, apaste, a foam, and combinations thereof for example.

Implementations of Amino Acid Compounds and Compositions mayconveniently be presented in unit dosage form. Unit dosage formulationsmay be those containing a daily dose or unit, a daily sub-dose, or anappropriate fraction thereof, of the administered components asdescribed herein.

A dosage unit may include an Amino Acid Compound or Composition. Inaddition, a dosage unit may include an Amino Acid Compound orComposition admixed with a pharmaceutically acceptable additive(s),and/or any combination thereof.

The dosage units may be in a form suitable for administration bystandard routes. In general, the dosage units may be administered, bynon-limiting example, by the topical (including buccal and sublingual),transdermal, oral, rectal, ophthalmic (including intravitreal orintracameral), nasal, vaginal, and/or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intratracheal,and epidural) routes and many other delivery methods and/or systemsknown to those of ordinary skill in the art. Implementations of an AminoAcid Compound or Composition may also be administered through use ofamphipathic lipid delivery systems (such as liposomes and unilamellarvesicles). Those of ordinary skill in the art will readily be able toselect additional pharmaceutically acceptable additives to enabledelivery of implementations of a pharmaceutical composition from thedisclosure in this document.

For the exemplary purposes of this disclosure, oral delivery may be aparticularly advantageous delivery route for administration to humansand animals of implementations of a pharmaceutical composition,optionally formulated with appropriate pharmaceutically acceptableadditives to facilitate administration.

Manufacture

Implementations of Amino Acid Nitrate and/or Nitrite Compounds orCompositions may be synthesized or created in a wide variety of manners,and may be made from a wide variety of materials. Those of ordinaryskill in the art will readily be able to select appropriate materialsand methods to manufacture and use the compounds and compositionsdisclosed herein.

Accordingly, although there are a variety of method implementations forproducing pharmaceutical compositions, for the exemplary purposes ofthis disclosure, a method implementation for producing an Amino AcidCompound may comprise: measuring specific quantities of Amino Acid,Nitric or Nitrous Acid and water or any other polar, easily evaporatedsolvent such as methanol, alcohol, pyridine, and the like mixed in aspecific order the measured quantities of Amino Acid, Nitric or NitrousAcid and water or solvent, and any additional pharmaceuticallyacceptable additives or inert ingredients, and then separating thepharmaceutical composition into discrete quantities for distributionand/or administration.

Measuring specific quantities of Amino Acid, Nitric or Nitrous Acid andwater or solvent, and pharmaceutically acceptable additives or inertingredients, may involve any number of steps and implementingcomponents, and measuring specific quantities of Amino Acid, Nitric orNitrous Acid and water or solvent, and pharmaceutically acceptableadditives or inert ingredients, may be accomplished readily from thisdisclosure. For the exemplary purposes of this disclosure, measuringspecific quantities of Amino Acid, Nitric or Nitrous Acid and water orsolvent, and pharmaceutically acceptable additives or inert ingredients,may comprise using a scale, a solid or liquid dispensing apparatus, orother measurement device capable of measuring solid mass or liquidvolume to produce a desired quantity of Amino Acid, Nitric or NitrousAcid and water or solvent, and pharmaceutically acceptable ingredient.

It should be appreciated that any of the components of particularimplementations of an Amino Acid Compound or Composition may be used assupplied commercially, or may be preprocessed by, by non-limitingexample, any of the methods and techniques of agglomeration, airsuspension chilling, air suspension drying, balling, coacervation,comminution, compression, pelletization, cryopelletization, extrusion,granulation, homogenization, inclusion Compoundation, lyophilization,melting, mixed, molding, pan coating, solvent dehydration, sonication,spheronization, spray chilling, spray congealing, spray drying, or otherprocesses known in the art depending in part on the dosage form desired.The various components may also be pre-coated or encapsulated as knownin the art. It will also be clear to one of ordinary skill in the artthat appropriate additives may also be introduced to the composition orduring the processes to facilitate the preparation of the dosage forms,depending on the need of the individual process.

Mixing the measured quantities of Amino Acid, Nitric or Nitrous Acid andwater or solvent, and pharmaceutically acceptable additives or inertingredients for Compounds, or mixing the measured quantities of AminoAcid, Nitrate and/or Nitrite sources, and pharmaceutically acceptableadditives or inert ingredients for Compositions, may involve any numberof steps and implementing components, and may be accomplished readilyfrom this disclosure.

For the exemplary purposes of this disclosure, mixing the measuredquantities of Amino Acid, Nitric or Nitrous Acid and water or solvent,and pharmaceutically acceptable additives or inert ingredients, maycomprise combining the measured quantities of m Amino Acid, Nitric orNitrous Acid and water or solvent, and pharmaceutically acceptableadditives or inert ingredients, under the influence of physical,ultrasonic, or electrostatic forces to create a desired degree ofintermingling and/or chemical reaction of the Amino Acid, Nitric orNitrous Acid and water or solvent and any pharmaceutically acceptableingredients. The mixed may be accomplished when the Amino Acid, Nitricor Nitrous Acid and water or solvent and/or any pharmaceuticallyacceptable ingredients are in a solid, liquid, or semisolid state.

Separating the Amino Acid Compound or Composition into discretequantities for distribution may involve any number of steps andimplementing components, and separating the Amino Acid Compound orComposition into discrete quantities for distribution may beaccomplished readily from this disclosure. For the exemplary purposes ofthis disclosure, separating the Amino Acid Compound or Composition intodiscrete quantities for distribution may involve utilizing a specificpiece of equipment, for example, a conventional tablet forming apparatusto shape the formed composition into individual tablets, each containinga desired dose of Amino Acid Compound or Composition. The separatingprocess may be accomplished when the Amino Acid Compound or Compositionis in a solid, liquid, or semisolid state.

Those of ordinary skill in the art will be able to readily selectmanufacturing equipment and pharmaceutically acceptable additives orinert ingredients to manufacture implementations of an Amino AcidCompound or Composition. For the exemplary purposes of this disclosure,some examples of pharmaceutically acceptable additives or inertingredients and manufacturing process are included below, particularlythose that relate to manufacture of implementations of an Amino AcidCompound or Composition in tablet form. Notwithstanding the specificexamples given, it will be understood that those of ordinary skill inthe art will readily appreciate how to manufacture implementations of anAmino Acid Compound or Composition according to the other methods ofadministration and delivery disclosed in this document.

Accordingly, compounds and Compositions may include a acceptableadditive (e.g. one of a solubilizer, an enzyme inhibiting agent, ananticoagulant, an antifoaming agent, an antioxidant, a coloring agent, acoolant, a cryoprotectant, a hydrogen bonding agent, a flavoring agent,a plasticizer, a preservative, a sweetener, a thickener, andcombinations thereof) and/or a acceptable carrier (e.g. one of anexcipient, a lubricant, a binder, a disintegrator, a diluent, anextender, a solvent, a suspending agent, a dissolution aid, anisotonization agent, a buffering agent, a soothing agent, an amphipathiclipid delivery system, and combinations thereof).

For example, a particular implementation of an Amino Acid Compound orComposition may include a lubricant. Lubricants are any anti-stickingagents, glidants, flow promoters, and the like materials that perform anumber of functions in tablet manufacture, for example, such asimproving the rate of flow of the tablet granulation, preventingadhesion of the tablet material to the surface of the dies and punches,reducing interparticle friction, and facilitating the ejection of thetablets from the die cavity. Lubricants may comprise, for example,magnesium stearate, calcium stearate, talc, and colloidal silica.

Particular implementations of an Amino Acid Compound or Composition mayalso include a binder. Binders are any agents used to impart cohesivequalities to powdered material through particle-particle bonding.Binders may include, for example, matrix binders (e.g. dry starch, drysugars), film binders (e.g. celluloses, bentonite, sucrose), andchemical binders (e.g. polymeric cellulose derivatives, such as methylcellulose, carboxy methyl cellulose, and hydroxy propyl cellulose); andother sugar, gelatin, non-cellulosic binders and the like.

Disintegrators may be used in particular implementations of an AminoAcid Compound or Composition to facilitate the breakup or disintegrationof tablets after administration. Disintegrators may include, forexample, starch, starch derivatives, clays (e.g. bentonite), algins,gums (e.g. guar gum), cellulose, cellulose derivatives (e.g. methylcellulose, carboxymethyl cellulose), croscarmellose sodium,croscarmellose cellulose, and other organic and inorganic materials.

Implementations of an Amino Acid Compound or Composition may includediluents, or any inert substances added to increase the bulk of theAmino Acid Compound to make a tablet a practical size for compression.Diluents may include, for example, calcium phosphate, calcium sulfate,lactose, mannitol, magnesium stearate, potassium chloride, and citricacid, among other organic and inorganic materials.

Buffering agents may be included in an Amino Acid Compound orComposition and may be any one of an acid and a base, where the acid is,for example, propionic acid, p-toluenesulfonic acid, salicylic acid,stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolicacid, or toluenesulfonic acid, and the base is, for example, ammoniumhydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, aluminum hydroxide, calcium carbonate, and other organic andinorganic chemicals.

With respect to delivery of particular implementations of an Amino AcidCompound or Composition, for the exemplary purposes of this disclosure,tablets may be utilized. Tablets are any solid pharmaceutical dosageform containing a pharmaceutically acceptable active agent or agents tobe administered with or without suitable pharmaceutically acceptableadditives and prepared either by compression or molding methods wellknown in the art. Tablets have been in widespread use and remain popularas a dosage form because of the advantages afforded both to themanufacturer (e.g., simplicity and economy of preparation, stability,and convenience in packaging, shipping, and dispensing) and the patient(e.g., accuracy of dosage, compactness, portability, blandness of taste,and ease of administration). Although tablets are most frequentlydiscoid in shape, they may also be round, oval, oblong, cylindrical,rectangular or triangular, for example. The tablets may be optionallyscored so that they may be separated into different dosages. They maydiffer greatly in size and weight depending on the amount of thepharmaceutically acceptable active agent or agents present and theintended route of administration. They are divided into two generalclasses, (1) compressed tablets, and (2) molded tablets.

Tablets and other orally discrete dosage forms, such as capsules,cachets, pills, granules, pellets, beads, and particles, for example,may optionally be coated with one or more enteric coatings, sealcoatings, film coatings, barrier coatings, compress coatings, fastdisintegrating coatings, or enzyme degradable coatings for example.Multiple coatings may be applied for desired performance. Further,dosage forms may be designed for, by non-limiting example, immediaterelease, pulsatile release, controlled release, extended release,delayed release, targeted release, synchronized release, or targeteddelayed release. For release/absorption control, carriers may be made ofvarious component types and levels or thicknesses of coats. Such diversecarriers may be blended in a dosage form to achieve a desiredperformance. In addition, the dosage form release profile may beeffected by a polymeric matrix composition, a coated matrix composition,a multi-particulate composition, a coated multi-particulate composition,an ion-exchange resin-based composition, an osmosis-based composition,or a biodegradable polymeric composition.

While manufacture of implementations of an Amino Acid Compound andComposition have been described in particular sequences of steps and/orin particular forms, it will be understood that such manufacture is notlimited to the specific order of steps or forms as disclosed. Any stepsor sequences of steps of manufacture of implementations of an Amino AcidCompound and Composition in any form are given as examples of possiblesteps or sequences of steps or potential forms and not as limitations,since many possible manufacturing processes and sequences of steps maybe used to manufacture Amino Acid Compound and Compositionimplementations in a wide variety of forms.

Use

Implementations of an Amino Acid Compound or Composition areparticularly useful in increasing bioabsorption and vasodilation inhumans and animals. However, implementations are not limited to usesrelating to bioabsorption or vasodilation modification, and the like.Rather, any description relating to the foregoing is for the exemplarypurposes of this disclosure. It will be understood that implementationsof an Amino Acid Compound or Composition may encompass a variety of usesand are not limited in their uses. For example, possible uses may be, bynon-limiting example, prevention of Nitrate tolerance, enhanced watersolubility, increased distribution to muscles, increased athleticperformance, and/or countering Nitric Oxide inhibiting effects ofcertain Amino Acids.

In conventional preparations of Nitrate compounds, “tolerance,” aparticular side effect, has been observed in many patients. This isunfortunate because the effectiveness of Nitrate on vasodilation is welldocumented. “Tolerance” occurs when a subject's reaction to Nitratedecreases so that larger doses are required to achieve the same effect.A Mar. 3, 2000 report in the British Journal of Pharmacology indicatesthat “tolerance to the dilator effects of nitrates remains a persistingtherapeutic problem.” Raymond J. MacAllister “Arginine and NitrateTolerance” available athttp://www.nature.com/bjp/journal/v130/n2/full/0703340a.html, thecontents of which are hereby incorporated herein by reference.

Empirical studies indicate that Nitrates are useful for theirvasolidating effects. Common Nitrates include nitroglycerin andisosorbide dinitrate. Nitrates exert their vasodilating effect throughtheir reduction to Nitrites. In vivo, Nitrates are reduced to Nitritesand, in the blood vessels' epithelial cells, Nitrite reacts with a thioldonor (mainly glutathione) to yield Nitric Oxide. Louis J. Ignarro,“After 130 years, the Molecular Mechanism of Action of Nitroglycerin isRevealed” (Jun. 11, 2002) available athttp://www.pnas.org/cgi/content/full/99/12/7816?ck=nck, the contents ofwhich are hereby incorporated herein by reference.

The Nitric Oxide inhibiting characteristics of the Amino Acid Glutaminehave been well documented in a number of studies. In particular, a Mar.28, 2006 report in the American Journal of Physiology has found thatGlutamine inhibits Nitric Oxide production by downregulation of eNOSsynthase. Masao Kakoki, et al. “Amino acids as Modulators ofEndothelium-Derived Nitric Oxide.” available athttp://ajprenal.physiology.org/cgi/content/full/291/2/F297, the contentsof which are hereby incorporated by reference.

A January 2006 Journal of Nutrition report indicates that the Amino AcidLeucine promotes anabolism and stimulates muscle protein synthesis.Michael J. Rennie, et al. “Branched-Chain Amino Acids as Fuels andAnabolic Signals in Human Muscle” available athttp://jn.nutrition.org/cgi/content/full/136/1/264S, the contents ofwhich are hereby incorporated by reference.

Empirical studies indicate that the Amino Acid Norvaline inhibits theenzyme arginase and thus decreases the rate of conversion of the AminoAcid Arginine to urea. Takeyori Saheki, et al. “Regulation of UreaSynthesis in Rat Liver” available athttp://jb.oxfordjournals.org/cgi/content/abstract/86/3/745?ijkey=5d134456b7443ca36c809269462276e532549798&keytype2=tf_ipsecsha,the contents of which are hereby incorporated by reference.

An October 2004 Journal of Nutrition report indicates that the AminoAcid Ornithine promotes anabolism and stimulates muscle proteinsynthesis. Michael J. Rennie, et al. “Branched-Chain Amino Acids asFuels and Anabolic Signals in Human Muscle” available athttp://jn.nutrition.org/cgi/content/full/136/1/264S, the contents ofwhich are hereby incorporated by reference.

Empirical studies indicate that the Amino Acids Beta-Beta Alanine andL-Histidine support carnosine production. M. Dunnett, “Influence of OralBeta-Beta Alanine and L-Histidine Supplementation on the CarnosineContent of the Gluteus Medius” Equine Veterinary Journal Supplement,available athttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10659307&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed,the contents of which are hereby incorporated by reference.

Empirical studies further indicate that the Amino Acids Beta Alanine andL-Histidine increase muscle power, recuperation and stamina. YoshihiroSuzuki “High Level of Skeletal Muscle Carnosine Contributes to theLatter Half of Exercise Performance During 30-S Maximal Cycle ErgometerSprinting” in the Japanese Journal of Physiology, available athttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12139778&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum,the contents of which are hereby incorporated by reference.

Accordingly, Applicants have discovered that the Arginine compoundaccording to the first implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Arginine, the singleadministration of Nitrates, or the single administration of Nitrites.Improved vasodilation may, in turn, provide better circulation anddistribution of Arginine in the body. Absorption may be improved sinceAmino Acid salts with inorganic acids are much more water soluble thansingle administration Amino Acids. Applicants have also discovered thatthe vasodilating effect of Arginine Nitrate manifests faster than thatof single-administration Arginine, and as fast as any nitrate, since theNO₃— group of the salt requires minimal conversion to yield NitricOxide. Additionally a much lesser dose may be required for vasodilationto take place, compared to the single administration of Arginine.Likewise, the development of tolerance to the nitrate component of themolecule may be prevented with the presence of Arginine. ArginineNitrate may promote vasodilation through production of Nitric Oxide bytwo different pathways, the Arginine citrullization pathway and thenitrate reduction pathway. Arginine Nitrate may likewise be more watersoluble than single administration Arginine.

Accordingly, Applicants have discovered that the Citrulline compoundaccording to the second implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Citrulline, the singleadministration of Nitrates, or the single administration of Nitrites.Improved vasodilation may, in turn, provide better circulation anddistribution of Citrulline in the body. Absorption may be improved sinceAmino Acid salts with inorganic acids are much more water soluble thansingle administration Amino Acids. Additionally a much lesser dose maybe required for vasodilation to take place, compared to the singleadministration of Citrulline or nitrates. Citrulline Nitrate is likewisemore water soluble than single administration Citrulline.

Accordingly, Applicants have discovered that the Creatine compoundaccording to the third implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Creatine, the singleadministration of Nitrates, or the single administration of Nitrites.Improved vasodilation may, in turn, provide better circulation anddistribution of Creatine in the body. Absorption may be improved sinceAmino Acid salts with inorganic acids are much more water soluble thansingle administration Amino Acids. Additionally a much lesser dose maybe required for vasodilation to take place, compared to the singleadministration of nitrates.

Enhancing a molecule's solubility can enhance it's bioavailability, rateof absorption by the GI tract, and as a result, it's concentration inthe muscle tissue and it's effectiveness. As we have established, thenitrate salts of creatine and other molecules are exceptionally moresoluble that their counterparts. Recent studies on creatine nitrate show1100% improved solubility over creatine monohydrate.

Study 1

Intrinsic Dissolution Profiles of Creatine Nitrate, Creatine Monohydrateand Buffered Creatine

Objective: The objective of this study was to determine the dissolutioncharacteristics of three different forms of commercially availablecreatine including creatine nitrate (CN), creatine monohydrate (CM) andbuffered creatine (BC) under different temperature and pH. Methods:Intrinsic dissolution studies were carried out at 37° C. and roomtemperature in pH 2.5 and 7.4 buffer using modified Wood's apparatus.CN, CM and BC samples (˜0.5 g) were compressed in the dies with constantsurface area of 1.21 cm2 using a Carver press at 2000 psi with a dwelltime of 10 sec. These dies were placed in the USP dissolution apparatus(type II) containing 140 ml of dissolution media, with paddle speed of50 rpm. Dissolution medium were collected at definite time intervalsover a period of 3 hours for CN and 7 hours for both CM and BC andanalyzed for creatine using a validated HPLC method. Results: A plot ofthe amount of creatine dissolved (mg)/surface area (cm2) versus timegives the slope (k′) which is directly proportional to the dissolutionrate constant. The k′ (mg/cm2 hr) values for CN, CM and BC in pH 2.5buffer at room temperature were 293.0±3.48, 59.1±2.06 and 71.1±0.59. At37° C. these k′ (mg/cm2 hr) values were 327.3±2.66, 97.9±0.88 and117.9±1.12, respectively. In pH 7.4 buffer, the k′ (mg/cm2 hr) valuesfor CN, CM and BC were 278.9±14.6, 52.1±0.22 and 50.6±0.95 at roomtemperature and 319.5±14.3, 86.0±5.05 and 96.9±9.28 at 37° C.,respectively. Conclusions: The dissolution rates of all three creatineforms were higher at 37° C. as compared to at room temperature. CM andBC showed a higher dissolution rate at pH 2.5 than that at pH 7.4,irrespective of temperature. However, the dissolution rate of CN was notaffected by the pH of the dissolution media. Comparison of thedissolution profiles for these three creatine forms clearly indicatedthat CN has the higher intrinsic dissolution rate constant as comparedto CM and BC irrespective of temperature and pH of the dissolutionmedia. Results of this study further predict a better bioavailability ofCN as compared to CM and BC.

Study 2

Chemical Stability of Creatine Nitrate, Creatine Monohydrate andBuffered Creatine in Solution

Objective: The objective of this study was to determine the chemicalstability of creatine nitrate (CN), creatine monohydrate (CM) andbuffered creatine (BC) under two different storage conditions (37° C. inpH 2.5 buffer and 40° C. in pH 6.8 buffer). Methods: A knownconcentration (˜10 mg/ml) of CN, CM and BC were prepared in both pH 2.5and pH 6.8 buffer and stored in stability chambers in screw cappedbottles at 37° C. and 40° C., respectively. Samples were collected atpredetermined time points and analyzed for creatine and degradationproducts if any, using a validated HPLC method. Changes in the pH,clarity and color of the samples were also determined. The order ofdegradation and rate constant were determined by graphical method.Results: The degradation rate constants (k) for CN, CM and BC at 37° C.in pH 2.5 buffer were 0.075±0.001, 0.119±0.011 and 0.108±0.002 (day-1)while that at 40° C. in pH 6.8 buffer were 0.115±0.001, 0.015±0.001 and0.013±0.002 (day-1), respectively. The pH of CN samples at 40° C. in pH6.8 buffer changed from 2.83±0.01 to 4.31±0.01 within a period of 12days. The pH changes noticed at 37° C. in pH 2.5 buffer samples over thesame period of time for CM, and BC were 3.08±0.01 to 4.12±0.01 and3.11±0.01 and 4.16±0.01, respectively. No significant change in pH wasobserved for the rest of the samples. No change in the color and theclarity was noticed over 12 days. Conclusions: All the creatine samplesfollowed first order degradation kinetics under both these experimentalconditions. The k value for CN was found to be higher at 40° C. in pH6.8 buffer as compared to at 37° C. in pH 2.5 buffer. However, both CMand BC showed a faster rate of degradation at 37° C. in pH 2.5 bufferthan at 40° C. in pH 6.8 buffer. The major degradation product detectedwas creatinine. For CN the increase in pH was higher at 40° C. in pH 6.8buffer as compared to 37° C. in pH 2.5 buffer. However, opposite effectwas noticed for both CM and BC.

Study 3

Equilibrium Solubility Studies of Creatine Nitrate, Creatine Monohydrateand Buffered Creatine

Ambrish Panditl, Pinal Mistryl, Pat Dib2, Alexander Nikolaidis3 AlekhaK. Dashl

Department of Pharmacy Sciences, Creighton University, Omaha, Nebr.68178. Department of Physiological Science UCLA. Aristotle University OfThessaloniki.

Objective: The objective of this study was to determine the equilibriumsolubility of creatine nitrate (CN), creatine monohydrate (CM) andbuffered creatine (BC) in water at room temperature as well as in pH 2.5buffer at room temperature and 37° C. Methods: Excess amount of samplewas added to the appropriate solvent and temperature was maintained andagitated at 150 rpm. The supernatant was collected after centrifugationat 24, 48, 72 hours till equilibration and analyzed by a HPLC method.Equilibration was confirmed when the solubility values of twoconsecutive time points were identical. The pH of the solution wasmonitored and Differential scanning calorimetry (DSC) thermograms of thesolid samples before solubility and of the lyophilized sample aftersolubility studies were compared. Results: The equilibrium solubility ofCN, CM and BC in water at room temperature was reached in 44 hours, andwas 210.3±4.82 mg/ml, 19.1±0.40 mg/ml and 19.2±0.55 mg/ml, respectively.However, solubility for CN, CM and BC in pH 2.5 buffer at roomtemperature was 208.2±6.01 mg/ml, 23.8±0.33 mg/ml and 21.2±0.09 mg/mland achieved within 72 hours for CN and in 48 hours for CM and BCsamples, respectively. At 37° C. and in pH 2.5 buffer, the equilibriumsolubility was reached within 24 hours for all samples and was325.9±6.10, 31.5±0.71 and 32.6±0.67 for CN, CM, and BC. The pH ofsolutions of CN, CM and BC in water at room temperature was 0.44±0.04,8.24±0.14 and 10.03±0.02 respectively. However, these values in pH 2.5buffer at room temperature were 1.31±0.02, 3.44±0.02 and 3.68±0.01 andat 37° C. this was 1.13±0.07, 3.86±0.47 and 4.42±0.05, respectively. DSCthermograms of the original samples and lyophilized samples wereidentical. Conclusions: The solubility of creatine nitrate was around 10fold higher than that of CM or BC under these experimental conditionsstudied, where as no significant difference in the solubility of CM andBC were noticed. There was an increase in solubility of each of thecreatine forms in pH 2.5 at a higher temperature. DSC analysis confirmedthat no phase change was noticed during these solubility studies.

The effectiveness of creatine for increasing athletic performance andimproving body composition and muscle anabolism and performance is verywell established. Such is also the case for BCAAs (leucine, isoleucine,and valine), taurine and carnitine. It is also well established that forthese molecules to have these effects, like all drugs, they must reachthe site of action, i.e. the muscle.

Creatine Nitrate & the Athlete

Creatine Nitrate excels beyond its superior solubility, stability, anddissolution. That's because Creatine Nitrate overcomes two primarydrawbacks of creatine monohydrate. First, creatine monohydrate resultsin extreme intra and extracellular water and sodium retention. Theintracellular water retention is favorable. Cosmetically speakinghowever, the extracellular water retention is an unfavorable effect, asan athlete's muscles develop a smooth, soft, and bloated appearance.Second and most importantly, the extreme extracellular water retentionmay restrict muscle growth. Functionally speaking, the extracellularwater retention may push back against muscle cells that are attemptingto expand in size.

Creatine Nitrate expels excess extracellular water and sodium retention,while simultaneously hydrating and supersaturating muscle cells withcreatine. This offers a HUGE benefit to athletes, encouraging musclecells to expand in size without resistance from extracellular fluid. Inaddition, athletes using Creatine Nitrate may achieve a leaner, drier,and harder look to their muscle tissue; a stark contrast to the puffyand bloated look created by creatine monohydrate. Creatine Nitratehowever is more than “Creatine Nitrate,” as the nitrate component offerstremendous functional advantages to athletes.

Nitrates provide substantial benefits to athletes and bodybuilders, assupported by clinical research. Nitrates are organic anions naturallyoccurring in the human diet, with close to 80% of dietary nitrates foundin vegetables. Fruits and processed meats represent additional sourcesof nitrates in the human diet. In fact, researchers at Michigan StateUniversity have suggested nitrates may be nutritious (13). So whatbenefit does supplementation with nitrates offer to athletes?

Today, nitric oxide and pre-workout nitric oxide performance enhancingformulas have grown in popularity. Nitric oxide formulas are used toincrease muscular “pumps,” vasodilation, and nutrient transport to themuscle to assist in greater aerobic performance and recovery. However,most formulas utilize the amino acid L-arginine, a precursor to nitricoxide, as their base. Recently, L-arginine has been proven to beineffective for elevating nitric oxide levels. L-arginine has also beenproven ineffective at enhancing athletic performance (9,10,11). YetL-arginine is present in nearly every single nitric oxide formula on themarket. Contrary to popular belief, most of the “pump” feelingexperienced by trainees is derived from an insulin increase followingL-arginine supplementation (1).

As recent clinical research confirms, the reduction of inorganic nitrate(NO3-) and nitrite (NO2-) in vivo results in nitric oxide production.Not only does nitrate generate nitric oxide, but nitrate and nitrite areinert end-products of nitric oxide oxidation. That is, nitrate convertsinto nitric oxide, and once oxidized, nitric oxide is recycled back intonitrate, which then has the potential to convert into nitric oxide onceagain. And the cycle continues to repeat itself. This creates anexciting alternative to nitric oxide production, and carries profoundimplications for the bodybuilding community.

A critical problem with nitric oxide is the short lifespan it has in thebody. In just a few seconds, the nitric oxide molecule can bemetabolized, and the athlete loses any benefit he/she may have received.A pump however must be sustained for several minutes, if not hours, inorder to result in those biochemical conditions required to stimulatemuscle hypertrophy. And nitrates are capable of elevating nitric oxideproduction for up to 8 hours.

Thus the use of nitrates represents an important alternative to theclassical L-arginine-NO-synthase pathway (2) so commonly attempted invarious sports supplement formulations.

The efficacy of nitrates in athletic performance is overwhelming in theclinical research. Nitrate consumption significantly enhances nitricoxide production, resulting in vasodilation, improved nutrientabsorption, increased athletic performance (3), and improved energeticfunction in working muscles during exercise (12). For example, duringlow and moderate intensity exercise by humans, supplementation withnitrates has been reported to reduce the amount of oxygen required.During high intensity athletic exercise, nitrate supplementationenhances tolerance to high intensity training, effectively extending the“time to exhaustion”(4).

Organic nitrates also function as permeation enhancers. This isbeneficial because enhanced permeation increases intestinal absorptionof all nutrients coingested. This may allow for a superior quantity ofanabolic nutrients to be absorbed and taken up into muscle cells,assisting athletes with the growth and repair of muscle tissue. Nitratesare even able to allow absorption of large macromolecules such asinsulin (5,6,7).

For decades, the pharmaceutical industry has used nitrates to inducedirect and rapid vasodilation. And today, clinical research is provingthat nitrates may produce beneficial effects on blood pressure andcardiovascular health (8). In fact, a recent clinical study investigatedthe effects of 5 times the amount of nitrates (1,316 mg per day for a 70kg adult) currently recommended by the World Health Organization (259 mgper day for a 70 kg adult) and showed no adverse health or safetyeffects. The study results revealed an average reduction in diastolicblood pressure by 4.5 mmHg. Effects on systolic blood pressure were notobserved (14,15).

Nitrates themselves offer many benefits to athletes. Combined with theclinical research behind creatine supporting creatine's positivebenefits to athletes, Creatine Nitrate is the first creatine to solve tothe solubility, stability, and dissolution challenges whilesimultaneously providing up to 8 hours of powerful vasodilation thatworkout enthusiasts demand!

REFERENCES

The following references are hereby incorporated herein by reference.

1. Glucose—and arginine-induced insulin secretion by human pancreatic13-cells: the role of HERG K+ channels in firing and release

2. Does NO metabolism play a role in the effects of vegetables inhealth?Nitric oxide formation via the reduction of nitrites andnitrates. Dina Ralt * Gertner Institute for Epidemiology and HealthPolicy Research, Tel Hashomer, Israel

3. Larsen F J, Weitzberg E, Lundberg J O, Ekblom B. Effects of dietarynitrate on oxygen cost during exercise. Acta Physiol (Oxf). 2007September; 191(1):59-66. Epub 2007 Jul. 17.

4. Stephen J. Bailey,1 Paul Winyard,2 Anni Vanhatalo,1 Jamie R.Blackwell,1 Fred J. DiMenna,1 Daryl P. Wilkerson,1 Joanna Tarr,2 NigelBenjamin,2 and Andrew M. Jones1. Dietary nitrate supplementation reducesthe O2 cost of low-intensity exercise and enhances tolerance tohigh-intensity exercise in humans. 1School of Sport and Health Sciencesand; 2Peninsula College of Medicine and Dentistry, University of Exeter,Exeter, United Kingdom

5. Fetih G, Habib F, Katsumi H, Okada N, Fujita T, Attia M, Yamamoto A.Excellent absorption enhancing characteristics of NO donors forimproving the intestinal absorption of poorly absorbable compoundcompared with conventional absorption enhancers.

6. Koichi Takahashia,* , Nanako Numataa, Natsumi Kinoshitaa, NaokiUtoguchib, Tadanori Mayumic, Nobuyasu Mizunoa. Characterization of theinfluence of nitric oxide donors on intestinal absorption ofmacromolecules. International Journal of Pharmaceutics 286 (2004) 89-97

7. Fetih G, Habib F, Okada N, Fujita T, Attia M, Yamamoto A. Nitricoxide donors can enhance the intestinal transport and absorption ofinsulin and [Asu(1,7)]-eel calcitonin in rats.

8. Supatra Porasuphatanaa, Pei Tsaib, Gerald M. Rosenb. The generationof free radicals by nitric oxide synthase. Comparative Biochemistry andPhysiology Part C 134 (2003) 281-289 1532-0456/03/$—see frontmatter_(—)2002 Elsevier Science Inc. All rights reserved. PII:S1532-0456{hacek over (Z)}02.00271-5 Review.

9. Olek R A et al. A single oral intake of arginine does not affectperformance during repeated Wingate anaerobic test. J Sports Med PhysFitness. 2010 March; 50(1):52-6.

10. Liu T H, Wu C L, Chiang C W, Lo Y W, Tseng H F, Chang C K. No effectof shortterm arginine supplementation on nitric oxide production,metabolism and performance in intermittent exercise in athletes. J NutrBiochem. 2008 Aug. 15. [Epub ahead of print]

11. Bescós R, Gonzalez-Haro C, Pujol P, Drobnic F, Alonso E, SantolariaM L, Ruiz O, Esteve M, Galilea P. Effects of dietary L-arginine intakeon cardiorespiratory and metabolic adaptation in athletes. Int J SportNutr Exerc Metab. 2009 August; 19(4):355-65.

12. Larsen F J, Weitzberg E, Lundberg J O, Ekblom B. Dietary nitratereduces maximal oxygen consumption while maintaining work performance inmaximal exercise. Free Radic Biol Med. 2010 Jan. 15; 48(2):342-7. Epub2009 Nov. 12.

13. American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.27131

14. Tanja Sobko, Claude Marcus, Mirco Govoni, Shigeru Kamiya. “Dietarynitrate in Japanese traditional foods lowers diastolic blood pressure inhealthy volunteers.” Nitric Oxide Volume 22, Issue 2, Pages 136-140

15.http://www.foodnavigator.com/Product-Categories/Preservativesand-acidulants/Dietary-nitrates-maybe-beneficial-for-heart-health-Study/?utm_source=Newsletter_Product&utm_medium=email&utm_campaign=Newsletter%2BProduct

Accordingly, Applicants have discovered that the Glutamine compoundaccording to the fourth implementation, when ingested, counters theNitric Oxide (NO—) inhibiting characteristics of Glutamine. Absorptionof Glutamine may be improved since Amino Acid salts with inorganic acidsare much more water soluble than single administration Amino Acids.Additionally a much lesser dose may be required for vasodilation to takeplace, compared to the single administration of nitrates. GlutamineNitrate may likewise be more water soluble than single administrationGlutamine.

Accordingly, Applicants have discovered that the Leucine compoundaccording to the fifth implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Leucine, the single administrationof Nitrates, or the single administration of Nitrites. Improvedvasodilation may, in turn, provide better circulation and distributionof Leucine in the body. Absorption may be improved since Amino Acidsalts with inorganic acids are much more water soluble than singleadministration Amino Acids. Additionally a much lesser dose may berequired for vasodilation to take place, compared to the singleadministration of nitrates. Leucine Nitrate is likewise more watersoluble than single administration Leucine.

Accordingly, Applicants have discovered that the Norvaline compoundaccording to the sixth implementation, when ingested, promotesvasodilation through the inhibition of arginase, while promoting NitricOxide formation via the nitrate mechanism. Improved vasodilation may, inturn, provide better circulation and distribution of Norvaline in thebody. Absorption may be improved since Amino Acid salts with inorganicacids are much more water soluble than single administration AminoAcids. Additionally a much lesser dose may be required for vasodilationto take place, compared to the single administration of nitrates.Norvaline Nitrate may likewise be more water soluble than singleadministration Norvaline.

Accordingly, Applicants have discovered that the Ornithine compoundaccording to the seventh implementation, when ingested, provides anadditional vasodilation mechanism, reducing the amount of Ornithineneeded and the amount of time needed for the vasodilating properties tomanifest. Improved vasodilation may, in turn, provide better circulationand distribution of Ornithine in the body. Absorption may be improvedsince Amino Acid salts with inorganic acids are much more water solublethan single administration Amino Acids. Applicants have also discoveredthat Ornithine Nitrate begins acting as fast as any other nitrate, sincethe NO₃— group of the salt requires minimal conversion to yield NitricOxide. Additionally, a much lesser dose may be required for vasodilationto take place, compared to the single administration of nitrates.Ornithine Nitrate may likewise be more water soluble than singleadministration Ornithine.

Accordingly, Applicants have discovered that the Histidine compoundaccording to the eighth implementation, when ingested, provides avasodilation mechanism. Vasodilation may, in turn, provide bettercirculation and distribution of Histidine in the body. Applicants havelikewise discovered that the Histidine compound according to the ninthimplementation, when ingested, promotes carnosine production, thusincreasing muscle power, endurance and recuperation. Absorption may beimproved since Amino Acid salts with inorganic acids are much more watersoluble than single administration Amino Acids. Applicants have alsodiscovered that Histidine Nitrate begins acting as fast as any othernitrate, since the NO₃— group of the salt requires minimal conversion toyield Nitric Oxide. Additionally, a much lesser dose may be required forvasodilation to take place, compared to the single administration ofnitrates. Histidine Nitrate may likewise be more water soluble thansingle administration Histidine.

Accordingly, Applicants have discovered that the Beta Alanine compoundaccording to the ninth implementation, when ingested, providesvasodilation. Vasodilation may, in turn, provide better circulation anddistribution of Beta Alanine in the body. Applicants have likewisediscovered that the Beta Alanine compound according to the tenthimplementation, when ingested, promotes carnosine production, thusincreasing muscle power, endurance and recuperation. Absorption may beimproved since Amino Acid salts with inorganic acids are much more watersoluble than single administration Amino Acids. Applicants have alsodiscovered that Beta Alanine Nitrate begins acting as fast as any othernitrate, since the NO₃— group of the salt requires minimal conversion toyield Nitric Oxide. Additionally, a much lesser dose may be required forvasodilation to take place, compared to the single administration ofnitrates. Beta Alanine Nitrate may likewise be more water soluble thansingle administration Beta Alanine.

Accordingly, Applicants have discovered that the Agmatine compoundaccording to the eighth implementation, when ingested, counteracts theNitric Oxide inhibiting effect of single administration Agmatine.Absorption may be improved since Amino Acid salts with inorganic acidsare much more water soluble than single administration Amino Acids.Applicants have also discovered that Agmatine Nitrate begins acting asfast as any other nitrate, since the NO₃— group of the salt requiresminimal conversion to yield Nitric Oxide. Agmatine Nitrate may likewisebe more water soluble than single administration Agmatine.

Accordingly, Applicants have discovered that not only do the foregoingamino acid nitrate or nitrite compounds provide the effects discussedabove, but that Amino Acid Compositions (amino acids mixed withindependent sources of nitrates and/or nitrites) enhancebioavailability, absorption, vasodilation, water solubility,distribution to muscles, and the like of certain Amino Acids, as well asprevent Nitrate tolerance and counter Nitric Oxide inhibiting effects ofcertain Amino Acids.

As demonstrated by Anjali Pradhan and Juan Vera, “Effect of Anions onthe Solubility of Zwitterionic AInino Acids”, Journal of Chemical andEngineering data, Vol 45, 140-143 (2000) (which is hereby incorporatedherein by reference), the co-existence of the nitrate ion can enhancethe solubility of various amino acids by 300-400%. Although the changein solubility is significantly lower than that of the case of a saltwith a nitrate, it is enough to make a difference in absorption in-vivo.

Furthermore, the nitrate ion enhances absorption of compounds by theintestine. Nitrates increase bioavailability by: increasing intestinalabsorption of nutrients; and increasing vasodilation and blood flow andblood is the carrier of the nutrients to cells. See for example, thefollowing references which are hereby incorporated herein by reference:Takahashi K et al. “Characterization of the influence of nitric oxidedonors on intestinal absorption of macromolecules.” Int J Pharm 2004;286:89-97; Fetih G et al. “Nitric oxide donors can enhance theintestinal transport and absorption of insulin and [Asu(1,7)]-eelcalcitonin in rats.” J Control Release 2005; 106:287-97; Fetih G et al.“Excellent absorption enhancing characteristics of NO donors forimproving the intestinal absorption of poorly absorbable compoundcompared with conventional absorption enhancers.” Drug MetabPharmacokinet 2006; 21:222-9; and Mitchell, G. E., Little, C. O., Jr. &Greathouse, T. R. (1964). “Influence of nitrate and nitrite, on carotenedisappearance from the rat intestine.” Life Sci. 4, 385.

Also, the nitrate ion can cause vasodilatation after reduction tonitrite and then nitric oxide, improve blood circulation, to the musclesand thus distribution of these compounds to the muscle, as well asoxygen distribution to the muscles. Muscle oxygen is needed to provideenergy which is needed for all muscle anabolic actions to take place aswell as for the active transport of above nutrients via the cellmembrane. See the following references which are hereby incorporatedherein by reference—Bailey, Stephen G. et al., “Dietary nitratesupplementation reduces the 02 cost of low-intensity exercise andenhances tolerance to high-intensity exercise in humans”, PresS. J ApplPhysiol (Aug. 6, 2009) and Bailey, Stephen G. et al., “Dietary nitratesupplementation enhances muscle contractile efficiency duringknee-extensor exercise in humans”, J Appl Physiol 109:135-148, 2010).

In these same references it is also very well described nitrate'spositive effect on athletic endurance and muscle strength. Oxygen isneeded by the body to produce energy which by itself is needed for allthe metabolic processes in the body, including those that Compositionsof the present disclosure are involved in. Thus co-administration ofnitrate ion with Compositions of the present disclosure furthermoreincreases their distribution to the muscle and their effectiveness.

Therefore, not only does the binding of nitrate salt with Compoundsimprove their bioavalability, absorption and effectiveness, but also theco-administration of nitrate through another nitrate salt, acid or anatural source of nitrate in a Composition of the present disclosureshall have similar effects, albeit lower than in the case of nitratebonded with the molecule.

Via all the above mechanisms, concomitant nitrate or nitriteadministration in a composition with an amino acid can substantiallyincrease the concentration of an amino acid in the target muscles (e.g.,Neuron cells for the congitive enhancement properties ofphenylalanine,carnitine,glycine, and tyrosine, and Muscle cells for theperformance enhancing properties of Agmatine Arginine, Beta Alanine,Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine,Norvaline, Ornithine and Taurine). In the case of Creatine, this isfurther enhanced by the nitrate's ability to preserve muscle Creatineloads.

Therefore, concomitant nitrate or nitrite administration in acomposition with an amino acid (just as with amino acid nitrate ornitrite compounds discussed previously) can improve mental focus,cognitive function, athletic and muscle performance, endurance, andstrength, and produces much greater synergistic results than the use ofonly an amino acid alone or a nitrate and a nitrite alone.

1. A method for increasing athletic performance in a human or animal,the method comprising administering to the human or animal apharmaceutically effective amount of an amino acid compositioncomprising at least one constituent selected from the group consistingof a nitrate, a nitrite, and both, and at least one constituent aminoacid selected from the group consisting of Arginine, Agmatine, BetaAlanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine,Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine,Lysine, Methionine, Proline, Tyrosine, and Phenylalanine.
 2. A methodfor increasing distribution of Amino Acids to muscles in a human oranimal, the method comprising administering to the human or animal apharmaceutically effective amount of an amino acid compositioncomprising at least one constituent selected from the group consistingof a nitrate, a nitrite, and both, and at least one constituent aminoacid selected from the group consisting of Arginine, Agmatine, BetaAlanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine,Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine,Lysine, Methionine, Proline, Tyrosine, and Phenylalanine.
 3. A methodfor increasing solubility of Amino Acids in a human or animal, themethod comprising administering to the human or animal apharmaceutically effective amount of an amino acid compositioncomprising at least one constituent selected from the group consistingof a nitrate, a nitrite, and both, and at least one constituent aminoacid selected from the group consisting of Arginine, Agmatine, BetaAlanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine,Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine,Lysine, Methionine, Proline, Tyrosine, and Phenylalanine.